Project Summary/Abstract Although stereoselective bond-forming reactions involving oxocarbenium ions are important methods in carbohydrate chemistry and organic synthesis, these reactions often do not proceed with the expected stereochemistry. For example, in many cases stereochemistry cannot be predicted either because there are no models to understand stereoselectivity (as in the case of medium-ring oxocarbenium ions) or that these models fail to accommodate deviations from expected selectivity (as observed for neighboring-group participation). To address the gaps in our understanding of these stereochemical models, the following specific aims will be pursued: (1) we will examine neighboring-group participation in stereoselective reactions of cyclic oxocarbenium ions; (2) we will extend the concept of neighboring-group participation to encompass systems that are not related to carbohydrates, including to solve problems in acyclic stereocontrol; and (3) we will establish that seven-membered ring electrophiles (oxocarbenium ions) and nucleophiles (enolates) can react stereoselectively. In the first Aim, we will use systems that share structural characteristics with carbohydrates to explain why neighboring group effects are not as strong as may be anticipated, a fact suggested by our preliminary studies. We will also extend our preliminary studies that suggest the CO2R group of sialic acids exerts little influence on the stability of oxocarbenium ions and the stereochemistry of their reactions. The second Aim will use systems that are not closely related to carbohydrates to address mechanistic questions in carbohydrate chemistry. The third Aim will pursue a stereochemical model to understand the reactions involved in seven-membered ring sugars, and we will expand preliminary studies that reactions involving seven- membered ring enolates are more selective than analogous reactions of six-membered ring enolates. These studies will be performed in collaboration with a theoretical chemist, Professor Jeffery Evanseck (Duquesne University), who is skilled in using computational methods to investigate reaction mechanisms. The proposed research is significant because it will enable researchers to predict the stereochemistry of bond-forming reactions commonly used for the synthesis of carbohydrates, natural products, and other biologically active compounds. The proposed research is innovative because we use systems that are not carbohydrates to develop stereoselective reactions that can be used in carbohydrate chemistry, medicinal chemistry, and natural product synthesis. These studies are relevant to human health because they will help medicinal chemists plan and execute the synthesis of biologically active compounds such as carbohydrates with precise control of three-dimensional structures.